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RU2208614C2 - Tetrahydro-gamma-carbolines and pharmaceutical composition based on thereof - Google Patents

Tetrahydro-gamma-carbolines and pharmaceutical composition based on thereof Download PDF

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RU2208614C2
RU2208614C2 RU2000109310/04A RU2000109310A RU2208614C2 RU 2208614 C2 RU2208614 C2 RU 2208614C2 RU 2000109310/04 A RU2000109310/04 A RU 2000109310/04A RU 2000109310 A RU2000109310 A RU 2000109310A RU 2208614 C2 RU2208614 C2 RU 2208614C2
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Людо Эдмонд Жозефин КЕННИС
Жозефус Каролус МЕРТЕНС
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Янссен Фармацевтика Н.В.
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

FIELD: organic chemistry, medicine, pharmacy. SUBSTANCE: invention relates to tetrahydro-gamma-carbolines of the formula (I)
Figure 00000002
where R1, R2, D, Alk and n are given in the invention claim. Invention describes also pharmaceutical composition for binding with receptors 5-HT2, 5-HT2a and α2 based on these compounds. Invention provides preparing novel compounds showing valuable biological properties. Invention can be used in medicine. EFFECT: valuable medicinal properties of compounds. 8 cl, 9 tbl, 14 ex

Description

Текст описания в факсимильном виде (см. графическую часть). Тт Description text in facsimile form (see graphic part). TT

Claims (7)

1. Тетрагидро-гамма-карболины формулы (I)
Figure 00000003

его N-оксидная форма, фармацевтически приемлемая соль присоединения или стереохимически изомерная форма,
в которой
R1 представляет водород, C1-6-алкил, арил или C1-6 алкил, замещенный арилом;
R2 представляет, каждый независимо, галоген, гидрокси, C1-6алкил или C1-6 алкилокси;
n=0 или 1;
Alk представляет C1-6 алкандиил;
D представляет радикал формулы
Figure 00000004

Figure 00000005

Figure 00000006

в которых каждый Х независимо представляет S или NR12;
R3 представляет водород, C1-6алкил, арил или арилC1-6aлкил;
R4 представляет водород, амино, моноили ди(C1-6алкил) амино или моно или ди(арил C1-6алкил) амино;
R5, R6, R7, R10, R11 и R12 каждый независимо представляет водород или C1-6алкил;
R8 и R9 каждый независимо представляет водород, C1-6алкил или арил; или
R4 и R5, взятые вместе, могут образовывать бивалентный радикал -R4-R5 - формулы
-СН2-СН2-СН2- (а-1);
-СН2-СН2-СН2-СН2- (а-2);
-СН=СН-СН2- (а-3);
-СН2-СН=СН- (а-4)
или
-СН=СН-СН=СН- (а-5);
где один или два атома водорода указанных радикалов (а-1)-(а-5), каждый независимо, может быть замещен галогеном, C1-6алкилом, трифторметилом или C1-6алкокси; или
-R4 -R5 - может представлять также
-S-CH2-CH2- (a-6);
-S-CH2-CH2-CH2- (а-7);
-S-CH=CH- (а-8);
-NH-CH=CH- (а-9);
-S-CH-=N- (а-10);
или
-СН=СН-О- (а-11);
где один атом водорода в указанных радикалах (а-6)-(а-11) может быть замещен C1-6алкилом; и
арил представляет фенил или фенил, замещенный галогеном или C1-6 алкилом.1. Tetrahydro-gamma-carbolines of the formula (I)
Figure 00000003

its N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof,
wherein
R 1 represents hydrogen, C 1-6 alkyl, aryl or C 1-6 alkyl substituted with aryl;
R 2 is each independently halo, hydroxy, C 1-6 alkyl or C 1-6 alkyloxy;
n is 0 or 1;
Alk is C 1-6 alkanediyl;
D represents a radical of the formula
Figure 00000004

Figure 00000005

Figure 00000006

in which each X independently represents S or NR 12 ;
R 3 represents hydrogen, C 1-6 alkyl, aryl or aryl C 1-6 alkyl;
R 4 represents hydrogen, amino, monoyl di (C 1-6 alkyl) amino or mono or di (aryl C 1-6 alkyl) amino;
R 5 , R 6 , R 7 , R 10 , R 11 and R 12 each independently represents hydrogen or C 1-6 alkyl;
R 8 and R 9 each independently represents hydrogen, C 1-6 alkyl or aryl; or
R 4 and R 5 taken together can form a bivalent radical —R 4 —R 5 - formulas
-CH 2 -CH 2 -CH 2 - (a-1);
-CH 2 -CH 2 -CH 2 -CH 2 - (a-2);
-CH = CH-CH 2 - (a-3);
-CH 2 -CH = CH- (a-4)
or
-CH = CH-CH = CH- (a-5);
where one or two hydrogen atoms of said radicals (a-1) to (a-5), each independently, may be substituted with halogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy; or
-R 4 -R 5 - may also represent
-S-CH 2 -CH 2 - (a-6);
-S-CH 2 -CH 2 -CH 2 - (a-7);
-S-CH = CH- (a-8);
-NH-CH = CH- (a-9);
-S-CH- = N- (a-10);
or
-CH = CH-O- (a-11);
where one hydrogen atom in these radicals (a-6) - (a-11) may be substituted with C 1-6 alkyl; and
aryl is phenyl or phenyl substituted with halogen or C 1-6 alkyl. 2. Соединение по п.1, в котором n=0 или 1, и R2 находится в 6-, 7- или 8-положении γ-карболинового фрагмента.2. The compound according to claim 1, in which n = 0 or 1, and R 2 is in the 6-, 7- or 8-position of the γ-carboline fragment. 3. Соединение по п.1 или 2, в котором R2 представляет галоген, гидрокси, C1-6алкил или C1-6алкилокси; n=0 или 1; Alk представляет С1-4алкандиил; D представляет радикал формулы (а), в которой R3 представляет C1-6алкил; R4 представляет амино; или -R4-R5 представляет радикал формулы (а-2) или (а-5), в которой один или два атома водорода, каждый независимо, может быть замещен галогеном, C1-6алкилом, трифторметилом или C1-6алкилокси, или -R4-R5-представляет радикал формулы (а-6), (а-7), (а-8), (а-9), (а-10) или (а-11), в которой один атом водорода может быть замещен C1-6алкилом, или радикал формулы (е), в которой Х представляет S или NR12 и R10 представляет водород, или радикал формулы (f), где Х представляет S или NR12.3. The compound according to claim 1 or 2, in which R 2 represents halogen, hydroxy, C 1-6 alkyl or C 1-6 alkyloxy; n is 0 or 1; Alk is C 1-4 alkanediyl; D represents a radical of formula (a) in which R 3 represents C 1-6 alkyl; R 4 is amino; or —R 4 —R 5 represents a radical of formula (a-2) or (a-5) in which one or two hydrogen atoms, each independently, may be substituted with halogen, C 1-6 alkyl, trifluoromethyl, or C 1-6 alkyloxy, or —R 4 —R 5 — represents a radical of the formula (a-6), (a-7), (a-8), (a-9), (a-10) or (a-11), wherein one hydrogen atom may be substituted with C 1-6 alkyl, or a radical of formula (e) in which X is S or NR 12 and R 10 is hydrogen, or a radical of formula (f), where X is S or NR 12 . 4. Соединение по п.1 или 2, в котором R1 представляет водород; n=0 или 1; R2 представляет галоген, C1-6алкил или C1-6алкокси; Alk представляет 1,2-этандиил и D представляет радикал формулы (а), в которой R3 представляет C1-6алкил, R4 представляет амино, R5 представляет C1-6алкил, или -R4-R5- представляет радикал формулы (а-2), (а-5), (а-6), (а-7), (а-8) или (а-9), в которой один атом водорода может быть замещен C1-6алкилом, или радикал формулы (f), в которой Х представляет NR12, и R11 представляет C1-6алкил.4. The compound according to claim 1 or 2, in which R 1 represents hydrogen; n is 0 or 1; R 2 represents halogen, C 1-6 alkyl or C 1-6 alkoxy; Alk is 1,2-ethanediyl and D is a radical of formula (a) in which R 3 is C 1-6 alkyl, R 4 is amino, R 5 is C 1-6 alkyl, or —R 4 —R 5 is a radical of the formula (a-2), (a-5), (a-6), (a-7), (a-8) or (a-9), in which one hydrogen atom can be substituted with C 1-6 alkyl, or a radical of formula (f) in which X is NR 12 and R 11 is C 1-6 alkyl. 5. Соединение по п.1 или 2, в котором R1 представляет водород; n=0 или 1; R2 представляет галоген или C1-6алкил; Alk представляет 1,2-этандиил, и D представляет радикал формулы (а), в которой R3 представляет C1-6алкил, R4 и R5, взяты вместе, образуя -R4-R5- формулы (а-2), (а-5), (а-6), (а-7) или (а-8), в которой один атом водорода может быть замещен C1-6алкилом.5. The compound according to claim 1 or 2, in which R 1 represents hydrogen; n is 0 or 1; R 2 represents halogen or C 1-6 alkyl; Alk is 1,2-ethanediyl, and D is a radical of formula (a) in which R 3 is C 1-6 alkyl, R 4 and R 5 are taken together to form —R 4 —R 5 - formulas (a-2 ), (a-5), (a-6), (a-7) or (a-8), in which one hydrogen atom may be substituted with C 1-6 alkyl. 6. Соединение по п.1, в котором R1 представляет водород метил, н-бутил, фенил, бензил или 4-фторфенил.6. The compound according to claim 1, in which R 1 represents hydrogen, methyl, n-butyl, phenyl, benzyl or 4-fluorophenyl. 7. Соединение по любому из пп.1-6, обладающее способностью связываться с рецепторами 5-НТ2, 5HT2a и α2.
8. Фармацевтическая композиция для связывания с рецепторами 5-НТ2, 5НТ2а и α2, включающая фармацевтически приемлемый носитель и в качестве активного ингредиента терапевтически эффективное количество соединения по любому из пп.1-6.7. The compound according to any one of claims 1 to 6, having the ability to bind to 5-HT 2 , 5HT 2a and α 2 receptors.
8. A pharmaceutical composition for binding to 5-HT 2 , 5HT 2a and α 2 receptors, comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 6.
RU2000109310/04A 1997-09-08 1998-09-01 Tetrahydro-gamma-carbolines and pharmaceutical composition based on thereof RU2208614C2 (en)

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CN106631941B (en) * 2016-12-30 2018-09-28 青岛瀚生生物科技股份有限公司 A kind of preparation method of -3 chlorphenyl methyl sulfide of 2- methyl
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ZA988161B (en) 2000-03-22
IL134894A (en) 2005-03-20
CZ297220B6 (en) 2006-10-11
ATE243209T1 (en) 2003-07-15
NO315236B1 (en) 2003-08-04
CN1269800A (en) 2000-10-11
EP1015451B1 (en) 2003-06-18
EE200000059A (en) 2000-10-16
CN1110496C (en) 2003-06-04
HK1029107A1 (en) 2001-03-23
JP2001515899A (en) 2001-09-25
MY129176A (en) 2007-03-30
EE04496B1 (en) 2005-06-15
TW531539B (en) 2003-05-11
CA2301807A1 (en) 1999-03-18
IL134894A0 (en) 2001-05-20
SK2992000A3 (en) 2001-03-12
AU752410B2 (en) 2002-09-19
NZ503096A (en) 2001-11-30
NO20000737L (en) 2000-05-08
HRP20000108A2 (en) 2000-12-31
CZ2000726A3 (en) 2000-07-12
PL339143A1 (en) 2000-12-04
ES2202902T3 (en) 2004-04-01
US20020103209A1 (en) 2002-08-01
ID23954A (en) 2000-06-08

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